OP0207 LIPOSOMAL ANTAGOMIR-155-5P RESTORES ANTI-INFLAMMATORY MACROPHAGES AND IMPROVES ARTHRITIS IN PRE-CLINICAL MODELS OF RHEUMATOID ARTHRITIS
Authors: A. Paoletti, L. Bineta, C. Catherine, G. Fan, S. Marie, J. Pascaud, R. Elodie, Y. Luxin, N. Lilian, A. Elmesmari, R. Franceline, H. Magali, P. David, R. Julien, F. Francois, G. Nocturne, N. Tsapis, I. Mcinnes, M. Kurowska-Stolarska, E. Fattal, X. Mariette
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> RA is the most frequent systemic autoimmune disease that primarily affects multiple joints and causes irreversible bone and cartilage destruction in the absence of treatment <sup>([1])</sup>. Monocytes-macrophages are key players in the pathogenesis of RA and accumulate in the synovial tissue. Besides resident macrophages, blood monocytes can differentiate into monocyte-derived-macrophages that may join the synovium and have different phenotypes and functions. The "classically activated macrophage phenotype" is considered to be pro-inflammatory and contribute to RA pathogenesis by secreting pro-inflammatory cytokines. The "alternatively activated macrophage phenotype" is considered to be regulatory and anti-inflammatory in tissues. Actually, there is a continuum from pro-inflammatory to anti-inflammatory macrophages, with high plasticity between the different states. We have previously shown that RA patients, and not patients with other inflammatory rheumatic diseases, have an impaired maturation of monocytes in anti-inflammatory-macrophages with increased differentiation in a pro-inflammatory-phenotype. We have found that an increased expression of miR-155 in monocytes/macrophages could be responsible for this defect and thus, could represent a new therapeutic target in RA <sup>([2])</sup>. <h3>Objectives</h3> Our aim is to assess if the defect of monocytes polarization in anti-inflammatory-macrophages and the impact of miR-155 in this defect are present in 2 pre-clinical models of RA: the CIA (collagen-induce-arthritis) and STA mice (Serum transfert arhritis), both in which macrophages infiltration of synovium play a key role in pathophysiology. Then, we have test a new therapeutic strategies to correct this defect using PEG-liposomes containing antagomiR-155-5p. <h3>Methods</h3> AntagomiR-155-5p or antagomiR-control were encapsulated in PEG-liposomes of 100 nm in size and -10mV in zeta potential with high antagomiR loading efficiency (above 80%). Mice were injected intravenously with 1,5nmol/100µL PEG-liposomes containing antagomiR-155-5p or control after induction of arthritis. <h3>Results</h3> As in humans, we found that monocytes defect in anti-inflammatory-macrophages was associated with an increase of miR-155-5p in both mouse models. Moreover, we demonstrated the biodistribution of tagged-PEG-liposomes to inflamed joints 1 hour after injection and as well as their subsequent liver's accumulation after 48 hours, indicative of hepatic clearance, in arthritic mice. Subsequently, we demonstrated that treatment with an antagomiR-155-5p encapsulated in PEG-liposomes was able to decrease joint inflammation, to restore bone-marrow monocytes polarization in anti-inflammatory-macrophages, to reduce immune cells infiltration in synovial tissues, to increase the CD206<sup>+</sup> and CD163<sup>+</sup> tissue infiltrating macrophages and to decrease expression of mRNAs target of miR-155-5p, without any significant functional change in other immune cells including splenic B and T cells. <h3>Conclusion</h3> The injection of antagomiR-155-5p encapsulated in PEG-liposomes allows delivering small RNA to monocytes/macrophages, lead to reduce joint inflammation in murine models of RA, providing a promising strategy in human disease. <h3>References</h3> [1]McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017 Jun 10;389(10086):2328-2337. [2]Paoletti A, Rohmer J, Ly B, Pascaud J, Rivière E, Seror R, Le Goff B, Nocturne G, Mariette X. Monocyte/Macrophage Abnormalities Specific to Rheumatoid Arthritis Are Linked to miR-155 and Are Differentially Modulated by Different TNF Inhibitors. J Immunol. 2019 Oct 1;203(7):1766-1775. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.